HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKepsilon and DDX3.

Abstract
Hepatitis B virus (HBV) infection remains one of the most serious health problems worldwide. Whilst studies have shown that HBV impairs interferon (IFN) production from dendritic cells in chronic hepatitis B patients, it remains unknown whether HBV inhibits IFN production in human hepatocytes. Using transient transfection assays in a primary human hepatocyte cell line (PH5CH8), this study demonstrated that HBV polymerase inhibits IFN-beta promoter activity induced by Newcastle disease virus, Sendai virus or poly(I : C) in a dose-dependent manner, whilst ectopic expression of the HBV core and X proteins had no effect on IFN-beta promoter activity. In addition, HBV polymerase blocked cellular IFN-beta expression and consequent antiviral immunity revealed by an infection protection assay. Furthermore, overexpression of key molecules on the IFN-beta induction axis, together with HBV polymerase, resulted in a block of IFN-beta promoter activity triggered by RIG-I, IPS-1, TRIF, TBK1 and IKKepsilon, but not by an IFN regulatory factor 3 dominant-positive mutant (IRF3-5D), suggesting that HBV polymerase prevents IFN-beta expression at the TBK1/IKKepsilon level. Further studies showed that HBV polymerase inhibited phosphorylation, dimerization and nuclear translocation of IRF3, in response to Sendai virus infection. Finally, it was shown that HBV polymerase-mediated dampening of the interaction between TBK1/IKKepsilon and DDX3 may be involved in the inhibitory effect on IFN-beta induction. Taken together, these findings reveal a novel role of HBV polymerase in HBV counteraction of IFN-beta production in human hepatocytes.
AuthorsShiyan Yu, Jieliang Chen, Min Wu, Hui Chen, Nobuyuki Kato, Zhenghong Yuan
JournalThe Journal of general virology (J Gen Virol) Vol. 91 Issue Pt 8 Pg. 2080-2090 (Aug 2010) ISSN: 1465-2099 [Electronic] England
PMID20375222 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Gene Products, pol
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • P protein, Hepatitis B virus
  • Receptors, Immunologic
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Virulence Factors
  • Interferon-beta
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase
  • DDX3X protein, human
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Poly I-C
Topics
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases (immunology, metabolism)
  • Gene Products, pol (physiology)
  • Hepatitis B virus (immunology, pathogenicity)
  • Hepatocytes (virology)
  • Humans
  • I-kappa B Kinase (metabolism)
  • Interferon Regulatory Factor-3 (antagonists & inhibitors)
  • Interferon-beta (biosynthesis)
  • Newcastle disease virus (immunology)
  • Poly I-C (immunology)
  • Protein Serine-Threonine Kinases (metabolism)
  • Receptors, Immunologic
  • Sendai virus (immunology)
  • Toll-Like Receptor 3 (immunology)
  • Transfection
  • Virulence Factors (physiology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: